Elevated BACH1 Contributes to Mitochondrial Succinylome Remodeling and Trophoblast Bioenergetic Dysfunction in Preeclampsia.

Abstract

Preeclampsia (PE) is a major pregnancy complication characterized by placental dysfunction and metabolic disturbances. Although mitochondrial abnormalities are frequently observed in PE, the upstream regulatory mechanisms remain incompletely understood. Here, we investigated the potential involvement of BACH1 in trophoblast dysfunction in PE and explored its association with mitochondrial metabolic alterations and protein succinylation. BACH1 expression was assessed in placental tissues and plasma samples from patients with PE, its functional effects were examined in trophoblast cell lines and BACH1 overexpression mouse models, and metabolic, bioenergetic, and succinylation-related alterations were evaluated using multi-omics and functional analyses. BACH1 expression was elevated in PE placentas and correlated with disease severity. In trophoblasts, BACH1 overexpression impaired proliferation, invasion, and trophoblast-mediated angiogenesis and was accompanied by mitochondrial and metabolic abnormalities, while quantitative succinylproteomic analysis revealed widespread alterations in mitochondrial protein succinylation. In vivo, BACH1 overexpression induced key PE-like features, including hypertension, fetal growth restriction, and placental abnormalities, and glycine supplementation partially rescued the trophoblast dysfunction associated with BACH1 overexpression. Together, evidence from clinical samples and experimental models suggests that BACH1 is associated with mitochondrial succinylation remodeling and trophoblast dysfunction in PE, supporting the hypothesis that BACH1-associated metabolic dysregulation and mitochondrial succinylation remodeling may contribute to PE pathogenesis. Further studies are required to establish the causal relevance and clinical significance of these mechanisms in human PE.

Authors

Jiacheng Xu, Lujia Sun, Miaomiao Chen, Bingdi Chao, Jie He, Hongli Liu, Dongni Huang, Jie Wang, Lumei Xie, Philip N Baker, Yu-Bin Ding, Hongbo Qi, Xin Luo

Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China, Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China, Joint International Research Laboratory of Reproduction and Development of the Chinese, Ministry of Education, Chongqing Medical University, Chongqing 400016, China.